Application of Visible-Residue Limit for Cleaning Validation

Pharmaceutical plants must have visually clean equipment to operate according to good manufacturing practices. Formulators must visually inspect manufacturing equipment for cleanliness before formulation work begins (1). Manufacturers establish and perform visible cleanliness and analytical methods to ensure regulatory compliance. An analyst conducts a visual inspection and confirms visible cleanliness before taking swab samples for chemical analysis (2). The formulator of the subsequent batch conducts a visual inspection before manufacturing work begins. A correlation between available analytical data and visible cleanliness of manufacturing equipment over an extended period of time can expand the practice of performing visual inspections in lieu of swab sampling.

Yet, the US Food and Drug Administration's Guide to Inspection of Validation of Cleaning Processes (3) and other literature (4) discount using a visible limit as the sole acceptance criterion for cleanliness. Conversely, Mendenhall concluded that visible cleanliness criteria were more rigid than quantitative calculations and are clearly adequate for determining cleanliness (5). Other recent articles describe the justification and application of a visible-residue limit (VRL) (6, 7).

Many research teams have established quantitative VRL levels. Fourman and Mullen determined a visible limit of ~100 μg per 2 x 2-in. swab area (8) or ~4 μg/cm2 . Jenkins and Vanderwielen observed residues as low as 1.0 μg/cm2 with a light source (9). Forsyth et al. determined <0.4- to >10-μg/cm2 VRLs for active pharmaceutical ingredients (APIs) and excipients (6).

The acceptable residue limit (ARL) for drug residue on manufacturing equipment surfaces can be determined on a health- and adulteration-based criterion (2, 9, 10). Toxicity data are the basis for a health-based ARL and cross contamination is the basis of an adulteration-based ARL. Typically the lower of the two limits is used for the ARL. If the VRL is quantitatively established and is lower than the ARL, then the VRL can be an acceptable measure of equipment cleanliness. For this study, the VRL was evaluated for several commercialized solid dosage formulations and late-phase development formulations.

Stainless steel was chosen for the surface material because most manufacturing equipment surfaces are made of this material. Representative stainless steel coupons (304 grade, 2B finish) were used for spotting purposes in the laboratory setting. Larger equipment size and increased viewing distance cause reflected and ambient light that affect visibility in the manufacturing facility. To simulate these conditions, a background of stainless steel was used when viewing the spotted coupons.

The type of solvent and its solubility were also factors that affected appearance. Methanol was chosen as the solvent for the sample preparations because it leaves no residue, minimizes residual sample rings, and provides adequate solubility for most substances tested. When solubility was not achieved, samples were immediately spotted using a suspension in methanol. The common solvent allowed for a tighter control over spot sizes and concentration. The sample volume was varied for concentration differences. This procedure obviated the need for serial sample dilutions, thereby saving time and solvent consumption. A complementary volume of methanol was added to each sample to achieve a constant spot volume.

The standard light intensity in a manufacturing facility is 750 lx. Actual levels differ from room to room depending on equipment size, configuration, location, and associated shadows caused by the equipment. The larger a facility's manufacturing equipment, the greater the difference in lighting levels compared with smaller pilot-plant equipment. Large machinery without interior lighting deepens the shadows. To compensate for this lighting condition, a portable light was used for inspection as necessary. Therefore, the lighting for this study ranged from 100 lx to the portable light's intensity. For low lighting levels, ambient fluorescent light provided the same type of light as that used in manufacturing plants.